Abstract:
:Mutations in genes affecting primary cilia cause ciliopathies, a diverse group of disorders often affecting skeletal development. This includes Jeune syndrome or asphyxiating thoracic dystrophy (ATD), an autosomal recessive skeletal disorder. Unraveling the responsible molecular pathology helps illuminate mechanisms responsible for functional primary cilia. We identified two families with ATD caused by loss-of-function mutations in the gene encoding adrenergic receptor kinase 1 (ADRBK1 or GRK2). GRK2 cells from an affected individual homozygous for the p.R158* mutation resulted in loss of GRK2, and disrupted chondrocyte growth and differentiation in the cartilage growth plate. GRK2 null cells displayed normal cilia morphology, yet loss of GRK2 compromised cilia-based signaling of Hedgehog (Hh) pathway. Canonical Wnt signaling was also impaired, manifested as a failure to respond to Wnt ligand due to impaired phosphorylation of the Wnt co-receptor LRP6. We have identified GRK2 as an essential regulator of skeletogenesis and demonstrate how both Hh and Wnt signaling mechanistically contribute to skeletal ciliopathies.
journal_name
EMBO Mol Medjournal_title
EMBO molecular medicineauthors
Bosakova M,Abraham SP,Nita A,Hruba E,Buchtova M,Taylor SP,Duran I,Martin J,Svozilova K,Barta T,Varecha M,Balek L,Kohoutek J,Radaszkiewicz T,Pusapati GV,Bryja V,Rush ET,Thiffault I,Nickerson DA,Bamshad MJ,Universitdoi
10.15252/emmm.201911739subject
Has Abstractpub_date
2020-11-06 00:00:00pages
e11739issue
11eissn
1757-4676issn
1757-4684journal_volume
12pub_type
杂志文章abstract::Autologous haematopoietic stem cell transplantation is highly efficient for the treatment of systemic autoimmune diseases, but its consequences for the immune system remain poorly understood. Here, we describe an optimized RNA-based technology for unbiased amplification of T cell receptor beta-chain libraries and use ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201100129
更新日期:2011-04-01 00:00:00
abstract::In this report, we describe the development of a modified adeno-associated virus (AAV) capsid and promoter for transduction of retinal ON-bipolar cells. The bipolar cells, which are post-synaptic to the photoreceptors, are important retinal targets for both basic and preclinical research. In particular, a therapeutic ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201404077
更新日期:2014-09-01 00:00:00
abstract::Resistance to tamoxifen is a clinically major challenge in breast cancer treatment. Although downregulation of estrogen receptor-alpha (ERα) is the dominant mechanism of tamoxifen resistance, the reason for ERα decrease during tamoxifen therapy remains elusive. Herein, we reported that Spalt-like transcription factor ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201910638
更新日期:2019-12-01 00:00:00
abstract::Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, gen...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201910288
更新日期:2019-09-01 00:00:00
abstract::Neuroblastoma (NB) is the most deadly extra-cranial solid tumour in children necessitating an urgent need for effective and less toxic treatments. One reason for the lack of efficacious treatments may be the inability of existing drugs to target the tumour-initiating or cancer stem cell population responsible for sust...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201000093
更新日期:2010-09-01 00:00:00
abstract::The majority of human colorectal cancers (CRCs) are initiated by mutations arising in the adenomatous polyposis coli (APC) tumour suppressor gene. However, a new class of non-APC mutated CRCs has been defined that have a serrated histopathology and carry the (V600E)BRAF oncogene. Here we have investigated the pathogen...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201000099
更新日期:2010-11-01 00:00:00
abstract::Germ-line mutations in the BRCA1 gene strongly predispose women to breast cancer (lifetime risk up to 80%). Furthermore, the BRCA1 protein is absent or present at very low levels in about one third of sporadic breast cancers. However, the mechanisms underlying BRCA1 somatic inactivation appear multiple and are still n...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201100136
更新日期:2011-05-01 00:00:00
abstract::Glycine transporters (GlyT1 and GlyT2) that regulate levels of brain glycine, an inhibitory neurotransmitter with co-agonist activity for NMDA receptors (NMDARs), have been considered to be important targets for the treatment of brain disorders with suppressed NMDAR function such as schizophrenia. However, it remains ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.202012632
更新日期:2021-01-11 00:00:00
abstract::Activation of non-shivering thermogenesis (NST) in brown adipose tissue (BAT) has been proposed as an anti-obesity treatment. Moreover, cold-induced glucose uptake could normalize blood glucose levels in insulin-resistant patients. It is therefore important to identify novel regulators of NST and cold-induced glucose ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201505610
更新日期:2016-03-01 00:00:00
abstract::Inherited familial Alzheimer's disease (AD) is characterized by small increases in the ratio of Aβ42 versus Aβ40 peptide which is thought to drive the amyloid plaque formation in the brain of these patients. Little is known however whether ageing, the major risk factor for sporadic AD, affects amyloid beta-peptide (Aβ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201200243
更新日期:2012-07-01 00:00:00
abstract::The Plasmodium-infected hepatocyte has been considered necessary to prime the immune responses leading to sterile protection after vaccination with attenuated sporozoites. However, it has recently been demonstrated that priming also occurs in the skin. We wished to establish if sterile protection could be obtained in ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201201677
更新日期:2013-02-01 00:00:00
abstract::Endothelial dysfunction is critically involved in the pathogenesis of pulmonary arterial hypertension (PAH) and that exogenously administered microRNA may be of therapeutic benefit. Lower levels of miR-483 were found in serum from patients with idiopathic pulmonary arterial hypertension (IPAH), particularly those with...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201911303
更新日期:2020-05-08 00:00:00
abstract::Mitochondrial diseases can arise from mutations either in mitochondrial DNA or in nuclear DNA encoding mitochondrially destined proteins. Currently, there is no cure for these diseases although treatments to ameliorate a subset of the symptoms are being developed. In this issue of EMBO Molecular Medicine, Khan et al (...
journal_title:EMBO molecular medicine
pub_type: 评论,杂志文章
doi:10.15252/emmm.201404179
更新日期:2014-06-01 00:00:00
abstract::Organismal ageing is a complex process driving progressive impairment of functionality and regenerative potential of tissues. Cellular senescence is a state of stable cell cycle arrest occurring in response to damage and stress and is considered a hallmark of ageing. Senescent cells accumulate in multiple organs durin...
journal_title:EMBO molecular medicine
pub_type: 杂志文章,评审
doi:10.15252/emmm.201810234
更新日期:2019-12-01 00:00:00
abstract::Disease modeling with induced pluripotent stem cells (iPSCs) is creating an abundance of phenotypic information that has become difficult to follow and interpret. Here, we report a systematic analysis of research practices and reporting bias in neurological disease models from 93 published articles. We find heterogene...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201708191
更新日期:2017-12-01 00:00:00
abstract::Fibroblast growth factors (FGFs) play key roles in the pathogenesis of different human diseases, but the cross-talk between FGFs and other cytokines remains largely unexplored. We identified an unexpected antagonistic effect of FGFs on the interferon (IFN) signaling pathway. Genetic or pharmacological inhibition of FG...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201911793
更新日期:2020-09-07 00:00:00
abstract::Follistatin-like 1 (Fstl1) is a secreted protein that is acutely induced in heart following myocardial infarction (MI). In this study, we investigated cell type-specific regulation of Fstl1 and its function in a murine model of MI Fstl1 was robustly expressed in fibroblasts and myofibroblasts in the infarcted area com...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201506151
更新日期:2016-08-01 00:00:00
abstract::Diabetes mellitus (DM) is a growing international concern. Considerable mortality and morbidity associated with diabetes mellitus arise predominantly from thrombotic cardiovascular events. Oxidative stress-mediated mitochondrial damage contributes significantly to enhanced thrombosis in DM A basal autophagy process ha...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201506046
更新日期:2016-07-01 00:00:00
abstract::Immunotherapeutic approaches are currently the most advanced treatments for Alzheimer's disease (AD). Antibodies against amyloid β-peptide (Aβ) bind to amyloid plaques and induce their clearance by microglia via Fc receptor-mediated phagocytosis. Dysfunctions of microglia may play a pivotal role in AD pathogenesis and...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201606370
更新日期:2016-09-01 00:00:00
abstract::Genomic data sharing is becoming more important as scientists join forces across borders in biomedical research for the benefit of patients and society. The EU's General Data Protection Regulation (GDPR) helps simplify sharing of such data at the European and international level. However, initial optimism has dried up...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201911421
更新日期:2020-03-06 00:00:00
abstract::5'AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201302734
更新日期:2014-04-01 00:00:00
abstract::Familial Mediterranean fever (FMF) is the most frequent hereditary systemic autoinflammatory syndrome. FMF is usually caused by biallelic mutations in the MEFV gene, encoding Pyrin. Conclusive genetic evidence lacks for about 30% of patients diagnosed with clinical FMF. Pyrin is an inflammasome sensor maintained inact...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201910547
更新日期:2019-11-07 00:00:00
abstract::The nucleoside adenosine is a potent regulator of vascular homeostasis, but it remains unclear how expression or function of the adenosine-metabolizing enzyme adenosine kinase (ADK) and the intracellular adenosine levels influence angiogenesis. We show here that hypoxia lowered the expression of ADK and increased the ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201607066
更新日期:2017-09-01 00:00:00
abstract::RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug-resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic myeloid leukaemia (CML...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201201760
更新日期:2013-03-01 00:00:00
abstract::Retinitis pigmentosa, caused predominantly by mutations in photoreceptor genes, currently lacks comprehensive treatment. We discover that retinal microglia contribute non-cell autonomously to rod photoreceptor degeneration by primary phagocytosis of living rods. Using rd10 mice, we found that the initiation of rod deg...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201505298
更新日期:2015-09-01 00:00:00
abstract::Migraine is a common disabling brain disorder. A subtype of migraine with aura (familial hemiplegic migraine type 2: FHM2) is caused by loss-of-function mutations in α2 Na(+),K(+) ATPase (α2 NKA), an isoform almost exclusively expressed in astrocytes in adult brain. Cortical spreading depression (CSD), the phenomenon ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201505944
更新日期:2016-08-01 00:00:00
abstract::The current seasonal inactivated influenza vaccine protects only against a narrow range of virus strains as it triggers a dominant antibody response toward the hypervariable hemagglutinin (HA) head region. The discovery of rare broadly protective antibodies against conserved regions in influenza virus proteins has pro...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201910938
更新日期:2020-05-08 00:00:00
abstract::Gene therapy critically relies on vectors that combine high transduction efficiency with a high degree of target specificity and that can be administered through a safe intravenous route. The lack of suitable vectors, especially for gene therapy of brain disorders, represents a major obstacle. Therefore, we applied an...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201506078
更新日期:2016-06-01 00:00:00
abstract::The serotonin 2C receptor regulates food uptake, and its activity is regulated by alternative pre-mRNA splicing. Alternative exon skipping is predicted to generate a truncated receptor protein isoform, whose existence was confirmed with a new antiserum. The truncated receptor sequesters the full-length receptor in int...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201506030
更新日期:2016-08-01 00:00:00
abstract::Sterile inflammation underlies many diseases of the cornea including serious chemical burns and the common dry eye syndrome. In search for therapeutic targets for corneal inflammation, we defined the kinetics of neutrophil infiltration in a model of sterile injury to the cornea and identified molecular and cellular me...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201200221
更新日期:2012-05-01 00:00:00